Nervous system injury can have devastating long-term effects on brain or nerve function, yet signaling pathways that regulate nervous system responses to injury, especially in early acute phases, remain poorly defined. In our previous work we sought to identify molecules required to drive axon degeneration after axotomy and identified dSarm/Sarm1 as a key signaling molecule that drives axon auto-destruction. In dsarm/Sarm1 null mutant flies or mice, severed distal axons do not degenerate and remain morphologically intact for weeks after injury. Understanding how dSarm/Sarm1 signals in axons is now a major focus for the field, but the vast majority of studies have focused on the final outcome of axotomy?axonal degeneration?which occurs many hours to days after axotomy. In preliminary work we discovered that nerve injury leads to rapid changes (within 2-3 hrs after injury) in axon transport in both severed axons and adjacent intact neurons, and a suppression of sensory signal transduction in intact neurons throughout the nerve. We wish to understand how injury signals spread throughout the nerve so quickly to activate these response (which we refer to as Phase 1 responses), and the roles that neurons and glia play in this process. Interestingly, we found that components of the dSarm signaling pathway, the Ca2+-driven Unc-76?Cacophony?CamK-II?dSarm signaling pathway, and components of the MAPK pathway play important roles within 3 hrs after injury to alter axonal cell biology and function. In addition, we found that the glial receptor Draper/MEGF10, functions in glia to activate Phase 1 responses in intact neurons (but not severed neurons) within 3 hrs after injury. In Aim 1 we will characterize this novel role for dSarm/Sarm1 and the axon death signaling machinery in regulation of early (Phase 1) responses in intact neurons and severed axons in a simple, genetically-tractable injured nerved, and how these signaling events alter neurophysiology. In Aim 2 we will perform similar studies to explore a novel role for the Unc-76?Cacophony?CamK-II?dSarm signaling pathway and MAPK signaling in axonal Phase 1 responses to nerve injury. In Aim 3 we will determine how nerve injury severity regulates neuronal and glial responses to injury, and how the Draper signaling pathway helps spread injury signals along a nerve to modulate nerve-wide changes in axon physiology. This work will provide important new insights into how axon death signaling molecules regulate acute responses to nerve injury, identify new molecules involved in injury signaling (Unc-76, Cacophony, CamK-II), clarify how MAPK signaling drives changes in axon biology after injury, and delineate exciting new roles for Draper/MEGF10 during the acute window of nerve responses to injury. Given that dSarm/Sarm1 and Draper/MEGF10 signaling pathways (and their functional roles) are highly conserved, our work will illuminate fundamental mechanisms of nervous system injury signaling that should have high relevance to human neural injury and neurological disease.